Site-specific amino acid D-isomerization of Tau R2 and R3 peptides changes the fibril morphology, resulting in attenuation of Tau aggregation inhibitor potency.
Site-specific amino acid D-isomerization of Tau R2 and R3 peptides changes the fibril morphology, resulting in attenuation of Tau aggregation inhibitor potency.
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DOI：
10.1016/j.bbrc.2023.02.073
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发表时间：
2023-02
影响因子：
3.1
通讯作者：
T. Murata;Genta Ito;N. Utsunomiya‐Tate
中科院分区：
文献类型：
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作者：
T. Murata;Genta Ito;N. Utsunomiya‐Tate
Tau是一种微管结合蛋白，是阿尔茨海默病患者大脑中神经元缠结的主要成分。原纤维形成后的Tau聚集诱导阿尔茨海默病发病机制。随着衰老，在几种组织中发生的蛋白质中D-异构化氨基酸的积累被认为与年龄相关的疾病有关。在神经元缠结中的Tau中也发现了D-异构化的Asp积累。我们以前证明了D-异构化的天冬氨酸内微管结合重复肽的Tau，Tau R2和R3的结构转变和原纤维形成的速度的影响。在此，我们研究了Tau聚集抑制剂对野生型Tau R2和R3肽以及含D-异构化Asp的Tau R2和R3肽的原纤维形成的效力。Tau R2和R3肽内的Asp的D-异构化减弱了抑制剂的效力。我们接下来通过电子显微镜研究了D-异构化的含Asp的Tau R2和R3肽的原纤维形态。D-异构化的含Asp的Tau R2和R3原纤维显示出与野生型肽显著不同的原纤维形态。我们的结果表明Tau R2和R3肽内的Asp的D-异构化影响原纤维形态，导致Tau聚集抑制剂的效力减弱。
Tau, a microtubule-binding protein, is a major component of neurofibrillary tangles in the brains of Alzheimer's disease patients. Tau aggregation following fibril formation induces Alzheimer's disease pathogenesis. The accumulation of D-isomerized amino acids in proteins that occurs in several tissues with aging is thought to be implicated in age-related diseases. D-isomerized Asp accumulation has also been found in Tau in neurofibrillary tangles. We previously demonstrated the effects of D-isomerization of Asp within microtubule-binding repeat peptides of Tau, Tau R2, and R3 on the rates of structural transition and fibril formation. Here, we investigated the potency of Tau aggregation inhibitors on fibril formation of wild-type Tau R2 and R3 peptides and D-isomerized Asp-containing Tau R2 and R3 peptides. D-isomerization of Asp within Tau R2 and R3 peptides attenuated the potency of inhibitors. We next investigated the fibril morphology of D-isomerized Asp-containing Tau R2 and R3 peptides by electron microscopy. D-isomerized Asp-containing Tau R2 and R3 fibrils showed significantly different fibril morphology from that of wild-type peptides. Our results indicate that D-isomerization of Asp within Tau R2 and R3 peptides affects fibril morphology, resulting in attenuation of the potency of Tau aggregation inhibitors.